This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to understand the way varenicline, a novel medication that works like nicotine in the brain, helps smokers to quit, through focused measures of potential psychological and physiological processes and events. Varenicline is an FDA-approved pharmacotherapy for smoking cessation that is believed to provide relief from craving and withdrawal by acting on the brain receptors for the neurotransmitter, acetylchlonie. However, no controlled sutdies have established the physiolocial and psychological processes that explain how varneicline helps smokers to quit. The main goal of the proposed pilot study is to evaluate and compare the effects of varenicline on subjective, cognitive, and physiological outcomes, using a randomized, placebo-controlled, double-blind between-groups design. In general, we expect that compared to placebo, those treated with varenicline will find smoking less reinforcing, will have less impaired cognition, less anxiety, and better stress tolerance, as assessed in the laboratory. A secondary goal is to validate hte utility of the laboratory models for the identification of future medications to help smokers to quit. We are requesting the use of a ventilatied room at the GCRC (since subjects will be smoking during sessions).